Emerging evidence suggests that combinatorial action of numerous biologically active compounds may be a valuable source in a variety of therapeutic applications. Several nutraceuticals have demonstrated to augment the efficacy of pharmacological approaches or provide physiological benefit to improve age-related decline. Recently, the possibilities of anti-ageing interventions have multiplied also to ameliorate the mitochondrial alterations in ageing-associated diseases. In this report, we approached a novel treatment strategy by combining two bioactive dietary constituents (resveratrol and equol) to determine their effect on mitochondrial function. Taking into account that the biological activities of resveratrol and equol has been observed in a wide range of biological processes, they were selected to examine whether combining them would be more effective to modulate mitochondrial function. In HUVEC cells our results demonstrate that the co-administration of these natural products increased mitochondrial mass and mitochondrial DNA content. Additionally, combined use of both compounds increased SIRT1 enzymatic activity and induced mitochondrial biogenesis factors such as PGC1-a, TFAM and NRF-1. Therefore, identification of this novel synergism may provide a new perspective for future treatments aiming to modulate the mitochondrial activity with implications in maintaining endothelial function which is crucial in the regulation of immune response. Further studies to discover the molecular details of this crosstalk and to identify new combinations of active compounds affecting the mitochondrial function will be extremely beneficial to prevent mitochondrial decline.